Fused imidazole derivatives as multidrug resistance modulators

ABSTRACT

This invention concerns the compounds of formula  
                 
 
     the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein the dotted line is an optional bond; n is 1 or 2; R 1  is hydrogen; halo; formyl; C 1-4 alkyl optionally substituted with hydroxy, C 1-4 alkyloxy, C 1-4 alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl; or a radical of formula —X—COOR 5 , —X—CONR 6 R 7  or —X—COR 10  wherein —X— is a direct bond, C 1-4 alkanediyl or C 2-6 alkenediyl; R 5  is hydrogen, C 1-12 alkyl, Ar, Het, C 1-6 alkyl substituted with C 1-4 alkyloxy, aryl or heteroaryl; R 6  and R 7  each independently are hydrogen or C 1-4 alkyl; R 2  is hydrogen, halo, C 1-4 alkyl, hydroxyC 1-4 alkyl, C 1-4 alkyloxycarbonyl, carboxyl, formyl or phenyl; R 3  is hydrogen, C 1-4 alkyl or C 1-4 alkyloxy; R 4  is hydrogen, halo, C 1-4 alkyl, C 1-4 alkyloxy or haloC 1-4 alkyl; Z is —CH 2 —, —CH 2 —CH 2 —, —CH═CH—, —CHOH—CH 2 —, —O—CH 2 —, —C(═O)—CH 2 — or —C(═NOH)—CH 2 —; —A—B— is a bivalent radical; A 1  is a direct bond, optionally substituted C 1-6 alkanediyl, C 1-6 alkanediyl-oxy-C 1-6 alkanediyl, carbonyl, C 1-6 alkanediylcarbonyl, optionally substituted C 1-6 alkanediyloxy; A 2  is a direct bond or C 1-6 alkanediyl; and Q is aryl. Processes for preparing said products, formulations comprising said products and their use as a medicine are disclosed, in particular for inhibiting or reversing the effects of multidrug resistance.

[0001] This invention relates to fused imidazole derivatives havingmultidrug resistance modulating properties, and processes for theirpreparation; it further relates to compositions comprising them, as wellas their use as a medicine.

[0002] Chemotherapy is one of the most frequently used forms of cancertherapy and has found clinical applications in the treatment of almostevery type of cancer. One of the major problems in cancer chemotherapyis the development of resistance to cytotoxic drugs. Patients who didrespond to a first course of chemotherapy frequently relapse becausetumor cells seem to develop resistance against chemotherapeutic agentsor may acquire resistance to a cytotoxic agent used in a previoustreatment. A tumor may also manifest resistance to a cytotoxic agent towhich it has not previously been exposed, that agent being unrelated bystructure or mechanism of action to any agent used in previoustreatments of the tumor. Examples of these effects can be seen in, forexample, haematological tumors (leukemias, lymphomas), renal carcinomaand breast carcinoma.

[0003] Analogously, certain pathogens may acquire resistance topharmaceutical agents used in previous treatments of the diseases ordisorders to which those pathogens give rise. Pathogens may alsomanifest resistance to pharmaceutical agents to which they have notpreviously been exposed. Examples of this effect include multidrugresistance forms of malaria, tuberculosis, leishmaniasis and amoebicdysentery.

[0004] The above phenomena by which cancer cells or pathogens becomeresistant to multiple drugs that have little similarity in theirstructure or mechanism of action, are referred to collectively asmultidrug resistance (MDR).

[0005] As used throughout the text, MDR modulators or compounds havingMDR modulating properties are defined as compounds which are able todecrease, avoid, eliminate, inhibit or reverse the effects of multidrugresistance.

[0006] Since MDR is a major problem for the chemotherapeutic approach ofthe above-mentioned disorders, compounds capable of inhibiting orreversing the effects of multidrug resistance would be very useful.

[0007] EP-0,518,435 and EP-0,518,434, published on Dec. 16, 1992,disclose fused imidazole compounds having antiallergic activity.WO-94/13680 published Jun. 23, 1994, discloses substitutedimidazo[1,2-a](pyrrolo, thieno and furano) [2,3-d]azepine derivativeshaving antiallergic activity. Also, WO 95/02600, published on Jan. 26,1995, discloses other piperidinyl- or piperidinylidene substitutedimidazoazepine derivatives also having antiallergic activity.

[0008] The compounds of the present invention differ from the citedart-known compounds structurally, by the nature of the substituents onthe nitrogen of the piperidine moiety, and pharmacologically by the factthat, unexpectedly, these compounds have MDR modulating properties.

[0009] This invention concerns compounds of formula

[0010] the N-oxide forms, the pharmaceutically acceptable addition saltsand the stereochemically isomeric forms thereof, wherein

[0011] the dotted line is an optional bond;

[0012] n is 1 or 2;

[0013] R¹ is hydrogen; halo; formyl; C₁₋₄alkyl; C₁₋₄alkyl substitutedwith 1 or 2 substituents each independently selected from hydroxy,C₁₋₄alkyloxy, C₁₋₄alkylcarbonyloxy, imidazolyl, thiazolyl or oxazolyl;or a radical of formula —X—CO—OR⁵ (a-1); —X—CO—NR⁶R⁷ (a-2); or —X—CO—R¹⁰(a-3);

[0014] wherein

[0015] —X— is a direct bond, C₁₋₄alkanediyl or C₂₋₆alkenediyl;

[0016] R⁵ is hydrogen; C₁₋₁₂alkyl; Ar; Het; C₁₋₆alkyl substituted withC₁₋₄alkyloxy, C₁₋₄alkyloxycarbonylC₁₋₄alkyloxy, Ar or Het;

[0017] R⁶ and R⁷ each independently are hydrogen or C₁₋₄alkyl;

[0018] R¹⁰ is imidazolyl, thiazolyl or oxazolyl;

[0019] R² is hydrogen, halo, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxycarbonyl, carboxyl, formyl or phenyl;

[0020] R³ is hydrogen, C₁₋₄alkyl or C₁₋₄alkyloxy;

[0021] R⁴ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyloxy or haloC₁₋₄alkyl;

[0022] Z is Z¹ or Z²;

[0023] wherein

[0024] Z¹ is a bivalent radical of formula —CH₂—, —CH₂—CH₂— or —CH═CH₂—;provided that when the dotted line is a bond, then Z¹ is other than—CH₂—;

[0025] Z² is a bivalent radical of formula —CHOH—CH₁₂—, —O—CH₂—,—C(═O)—CH₂— or —C(═NOH)—CH₂—;

[0026] —A—B— is a bivalent radical of formula —Y—CR⁸═CH— (b-1);—CH═CR⁸—Y— (b-2); —CH═CR⁸—CH═CH— (b-3); —CH═CH—CR⁸═CH— (b-4); or—CH═CH—CH═CR⁸— (b-5);

[0027] wherein

[0028] each R⁸ independently is hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyloxy,hydroxyC₁₋₄alkyl, hydroxycarbonylC₁₋₁₄alkyl, formyl, carboxyl, ethenylsubstituted with carboxyl, or ethenyl substituted withC₁₋₁₄alkyloxycarbonyl;

[0029] each Y independently is a bivalent radical of formula —O—, —S— orR wherein R⁹ is hydrogen, C₁₋₄alkyl or C₁₋₄alkylcarbonyl;

[0030] —A¹— is a direct bond; C₁₋₆alkanediyl;C₁₋₆alkanediyl-oxy-C₁₋₆alkanedlyl; C₁₋₆alkanediyloxy; carbonyl;C₁₋₆alkanediylcarbonyl; C₁₋₆alkanediyloxy substituted with hydroxy; orC₁₋₆alkanediyl substituted with hydroxy or ═NOH;

[0031] —A²— is a direct bond or C₁₋₆alkanediyl;

[0032] Q is phenyl; phenyl substituted with one or two substituentsselected from hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy orhaloC₁₋₄alkyl; naphthalenyl; naphthalenyl substituted with one or twosubstituents selected from hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy orhaloC₁₋₄alkyl; pyridinyl; pyridinyl substituted with one or twosubstituents selected from hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy orhaloC₁₋₄alkyl; quinolinyl; or quinolinyl substituted with one or twosubstituents selected from hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy orhaloC₁₋₄alkyl;

[0033] Ar is phenyl or phenyl substituted with 1, 2 or 3 substituentseach independently selected from hydrogen, halo, C₁₋₄alkyl orC₁₋₄alkyloxy;

[0034] Het is furanyl; furanyl substituted with C₁₋₄alkyl, C₁₋₄alkyloxyor hydroxyC₁₋₄alkyl; oxazolyl; oxazolyl substituted with C₁₋₄alkyl orC₁₋₄alkyloxy; or quinolinyl.

[0035] As used in the foregoing definitions and hereinafter, halo isgeneric to fluoro, chloro, bromo and iodo; C₁₋₄alkyl defines straightand branched chain saturated hydrocarbon radicals having from 1 to 4carbon atoms such as, for example, methyl, ethyl, propyl, butyl,1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like; C₁₋₆alkylincludes C₁₋₄alkyl and the higher homologues thereof having from 5 to 6carbon atoms such as, for example, pentyl, hexyl, 3-methylbutyl,2-methylpentyl and the like; C₁₋₁₂alkyl includes C₁₋₆alkyl and thehigher homologues thereof having from 7 to 12 carbon atoms such as, forexample, heptyl, octyl, nonyl, decyl and the like; C₁₋₄alkanediyldefines bivalent straight and branched chain saturated hydrocarbonradicals having from 1 to 4 carbon atoms such as, for example,methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl and the like;C₁₋₅alkanediyl includes C₁₋₄alkanediyl and the higher homologues thereofhaving 5 carbon atoms such as, for example, 1,5-pentanediyl and thelike; C₁₋₆alkanediyl includes C₁₋₅alkanediyl and the higher homologuesthereof having 6 carbon atoms such as, for example, 1,6-hexanediyl andthe like; C₂₋₆alkenyl defines straight and branched chain hydrocarbonradicals containing one double bond and having from 2 to 6 carbon atomssuch as, for example, ethenyl, 2-propenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 3-methyl-2-butenyl, and the like; C₂₋₆alkenediyl definesstraight and branched chain hydrocarbon radicals containing one doublebond and having from 2 to 6 carbon atoms such as, for example,ethenediyl, 2-propenediyl, 3-butenediyl, 2-pentenediyl, 3-pentenediyl,3-methyl-2-butenediyl, and the like; haloC₁₋₄alkyl is defined as mono-or polyhalosubstituted C₁₋₄alkyl; C₁₋₆alkanediyl-oxy-C₁₋₆alkanediyldefines bivalent radicals of formula such as, for example,—CH₂—CH₂—O—CH₂—CH₂—, —CH₂—CH(CH₂CH₃)—O—CH(CH₃)—CH₂—, —CH(CH₃)—O—CH₂— andthe like.

[0036] Whenever the bivalent radical Al is defined as aC₁₋₆alkanediylcarbonyl or C₁₋₆alkanediyloxy, preferably theC₁₋₆alkanediyl part of said radicals is connected to the nitrogen atomof the piperidine ring.

[0037] Pyridinyl and quinolinyl in the definition of Q are preferablyconnected to A² by a carbon atom.

[0038] Whenever Z is defined as Z², the —CH₂— moiety of said bivalentradical is preferably connected to the nitrogen of the imidazole ring.

[0039] Wherever R¹ or R¹⁰ is defined as imidazolyl, thiazolyl oroxazolyl, said substituents are preferably connected by a carbon atom tothe rest of the molecule.

[0040] The compounds where Z is —CH₂— and the optional bond is presentare excluded by proviso because the tricyclic moiety in such compoundsspontaneously aromatizes, thereby losing its multidrug resistancemodulating properties.

[0041] The pharmaceutically acceptable addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicacid addition salt forms which the compounds of formula (I) are able toform. The latter can conveniently be obtained by treating the base formwith such appropriate acid. Appropriate acids comprise, for example,inorganic acids such as hydrohalic acids, e.g. hydrochloric orhydrobromic acid; sulfuric; nitric; phosphoric and the like acids; ororganic acids such as, for example, acetic, propanoic, hydroxyacetic,lactic, pyruvic, oxalic, malonic, succinic (i.e. butanedioic acid),maleic, fumaric, malic, tartaric, citric, methanesulfonic,ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,p-aminosalicylic, pamoic and the like acids.

[0042] The pharmaceutically acceptable addition salts as mentionedhereinabove are meant to comprise the therapeutically active non-toxicbase addition salt forms which the compounds of formula (I) are able toform. Examples of such base addition salt forms are, for example, thesodium, potassium, calcium salts, and also the salts withpharmaceutically acceptable amines such as, for example, ammonia,alkylamines, benzathine, N-methyl-D-glucamine, hydrabamine, amino acids,e.g. arginine, lysine.

[0043] Conversely said salt forms can be converted by treatment with anappropriate base or acid into the free acid or base form.

[0044] The term addition salt as used hereinabove also comprises thesolvates which the compounds of formula (I) as well as the saltsthereof, are able to form. Such solvates are for example hydrates,alcoholates and the like.

[0045] The term stereochemically isomeric forms as used hereinbeforedefines the possible different isomeric as well as conformational formswhich the compounds of formula (I) may possess. Unless otherwisementioned or indicated, the chemical designation of compounds denotesthe mixture of all possible stereochemically and conformationallyisomeric forms, said mixtures containing all diastereomers, enantiomersand/or conformers of the basic molecular structure. All stereochemicallyisomeric forms of the compounds of formula (I) both in pure form or inadmixture with each other are intended to be embraced within the scopeof the present invention.

[0046] Some compounds of the present invention may exist in differenttautomeric forms and all such tautomeric forms are intended to beincluded within the scope of the present invention. For instance,compounds of formula (I) wherein Q is pyridinyl or quinolinylsubstituted with hydroxy, may exist in their corresponding tautomericform.

[0047] The N-oxide forms of the compounds of formula (I) are meant tocomprise those compounds of formula (I) wherein one or several nitrogenatoms are oxidized to the so-called N-oxide, particularly those N-oxideswherein the piperidine-nitrogen is N-oxidized.

[0048] A first group of interesting compounds consists of thosecompounds of formula (I) wherein one or more of the followingrestrictions apply:

[0049] a) —A—B— is a bivalent radical of formula (b-2), (b-3) or (b-4);or

[0050] b) Z is Z¹ wherein Z¹ is a bivalent radical of formula —CH₂—CH₂—or —CH₂—; or

[0051] c) —A¹— is C₁₋₆alkanediyl, C₁₋₆alkanediyloxy, carbonyl, C1₆alkanediyloxy substituted with hydroxy, or C₁₋₆alkanediyl substitutedwith hydroxy; in particular —A¹— is C₁₋₆alkanediyl; or

[0052] d) —A²— is a direct bond or C₁₋₆alkanediyl; in particular —A²— isC₁₋₆alkainediyl;

[0053] e) Q is phenyl, naphthalenyl, pyridinyl or quinolinyl, andoptionally said Q is substituted with halo, C₁₋₆alkyl or C₁₋₆alkyloxy;

[0054] f) R¹ is hydrogen, halo, formyl, C₁₋₄alkyl substituted withhydroxy, or a radical of formula (a-1) wherein X is a direct bond orC₁₋₄alkanediyl and R⁵ is hydrogen, C₁₋₁₂alkyl, Ar or C₁₋₆alkylsubstituted with Het;

[0055] g) R² is hydrogen, halo, C₁₋₄alkyl, formyl, hydroxyC₁₋₄alkyl orC₁₋₄alkyloxycarbonyl;

[0056] h) R³ is hydrogen;

[0057] i) R⁴ is hydrogen, halo, C₁₋₆alkyl or C₁₋₆alkyloxy.

[0058] A second group of interesting compounds consists of thosecompounds of formula (I) wherein one or more of the followingrestrictions apply :

[0059] a) —A—B— is a bivalent radical of formula (b-2), (b-3) or (b-4);or

[0060] b) Z is Z² wherein Z² is a bivalent radical of formula—C(═O)—CH₂—; or

[0061] c) —A¹— is C₁₋₆alkanediyl, C₁₋₆alkanediyloxy, carbonyl,C₁₋₆alkanediyloxy substituted with hydroxy, or C₁₋₆alkanediylsubstituted with hydroxy; in particular —A¹— is C₁₋₆alkanediyl; or

[0062] d) —A²— is a direct bond or C₁₋₆alkanediyl; in particular —A²— isC₁₋₆alkanediyl;

[0063] e) Q is phenyl, naphthalenyl, pyridinyl or quinolinyl, andoptionally said Q is substituted with halo, C₁₋₆alkyl or C₁₋₆alkyloxy;

[0064] f) R¹ is hydrogen, halo, formyl, C₁₋₄alkyl substituted withhydroxy, or a radical of formula (a-1) wherein X is a direct bond orC₁₋₄alkanediyl and R⁵ is hydrogen, C₁₋₁₂alkyl, Ar or C₁₋₆alkylsubstituted with Het;

[0065] g) R² is hydrogen, halo, C₁₋₄alkyl, formyl, hydroxyC₁₋₄alkyl orC₁₋₄alkyloxycarbonyl;

[0066] h) R³ is hydrogen;

[0067] i) R⁴ is hydrogen, halo, C₁₋₆alkyl or C₁₋₆alkyloxy.

[0068] A particular group of compounds are those compounds of formula(I) wherein —A—B— is a bivalent radical of formula (b-2), (b-3) or (b-4)wherein R⁸ is hydrogen or halo; Z is —CH₂—CH₂—; —A¹— is —CH₂—CH₂—,—CH₂—CH₂—CH₂— or —O—CH₂—CH₂—; A²— is —CH₂— and the dotted line is abond.

[0069] Another particular group of compounds are those compounds offormula (I) wherein Q is 2-quinolinyl, 1-naphthalenyl, 2-naphthalenyl,phenyl or 2-pyridinyl and said Q is optionally substituted withC₁₋₄alkyl, halo, haloC₁₋₄alkyl or C₁₋₄alkyloxy.

[0070] A further particular group are those compounds of formula (I)wherein Q is 2-quinolinyl, 1-naphthalenyl, 2-naphthalenyl,6-methyl-2-quinolinyl, 6-chloro-2-pyridinyl, 4-methoxyphenyl,3,5-dimethylphenyl, 3,5-difluorophenyl, or3,5-bis(trifluoromethyl)phenyl.

[0071] Preferred compounds are those compounds of formula (I) wherein Zis —CH₂—CH₂—; —A—B— is —CH═CH—CH═CH—; —A¹— is —CH₂—CH₂— or —O—CH₂—CH₂—;—A²— is —CH₂—; R¹ is hydrogen, halo, formyl or a radical of formula(a-1) wherein X is a direct bond and R⁵ is hydrogen, C₁₋₁₂alkyl, Ar orC₁₋₆alkyl substituted with Het; R² is hydrogen, C₁₋₄alkyl, formyl orC₁₋₄alkyloxycarbonyl; R³ is hydrogen; R⁴ is hydrogen or C₁₋₄alkyloxy andthe dotted line is a bond.

[0072] Most preferred compounds of formula (I) are

[0073] methyl6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;

[0074] dimethyl6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-2,3-dicarboxylate;

[0075] ethyl6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;

[0076] methyl11-[1-[[3,5-dimethoxy-4-(2-quinolinylmethoxy)phenyl]methyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;

[0077] methyl6,11-dihydro-11-[1-[3-[4-(2-quinolinylmethoxy)phenyl]propyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;

[0078] methyl6,11-dihydro-11-[1-[2-[4-(2-naphthalenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;

[0079] methyl6,11-dihydro-11-[1-[2-[4-(phenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; and

[0080] methyl6,11-dihydro-11-[1-[2-[4-(1-naphthalenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;the stereoisomeric forms and

[0081] the pharmaceutically acceptable addition salts thereof.

[0082] In the following paragraphs there are described different ways ofpreparing the compounds of formula (I). In order to simplify thestructural formulae of the compounds of formula (I) and theintermediates intervening in their preparation, the fused imidazolemoiety will be represented by the symbol T hereinafter.

[0083] The compounds of the present invention can generally be preparedby N-alkylating an intermediate of formula (III) wherein W is anappropriate leaving group such as, for example, chloro, bromo,methanesulfonyloxy or benzenesulfonyloxy, with an intermediate offormula (II). The reaction can be performed in a reaction-inert solventsuch as, for example, ethanol, dichloromethane, methyl isobutylketone orN,N-dimethylformamide, and in the presence of a suitable base such as,for example, sodium carbonate, sodium hydrogen carbonate ortriethylamine. Stirring may enhance the rate of the reaction. Thereaction may conveniently be carried out at a temperature rangingbetween room temperature and reflux temperature.

[0084] Compounds of formula (I) may also be prepared by O-alkylating anintermediate of formula (V) with an intermediate of formula (IV),wherein W¹ is an appropriate leaving group such as, for example, chloro,bromo, methanesulfonyloxy or benzenesulfonyloxy. The reaction can beperformed in a reaction-inert solvent such as, for example,N,N-dimethylformamide, and in the presence of a suitable base such as,for example, sodium hydride, preferably at a temperature ranging betweenroom temperature and reflux temperature.

[0085] Compounds of formula (I) wherein —A^(1′)— representsC₁₋₆alkanediyl, C₁₋₆alkanediyloxy, C₁₋₆alkanediyloxyC₁₋₆alkanediyl, saidcompounds being represented by formula (I-i), may be prepared byreductive N-alkylation of an intermediate of formula (III) with anintermediate of formula (XIX). In said intermediate (XIX), —A^(1″)—represents a direct bond, C₁₋₅alkanediyl, C₁₋₅alkanediyloxy or aC₁₋₆alkanediyl-oxyC₁₋₅alkanediyl moiety whereby the formyl group isbonded on the C₁₋₅alkanediyl part.

[0086] Said reductive N-alkylation may be performed in a reaction-inertsolvent such as, for example, dichloromethane, ethanol, toluene or amixture thereof, and in the presence of a reducing agent such as, e.g.sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride.It may also be convenient to use hydrogen as a reducing agent incombination with a suitable catalyst such as, for example,palladium-on-charcoal or platinum-on-charcoal. In case hydrogen is usedas reducing agent, it may be advantageous to add a dehydrating agent tothe reaction mixture such as, for example, aluminium tert-butoxide. Inorder to prevent the undesired further hydrogenation of certainfunctional groups in the reactants and the reaction products, it mayalso be advantageous to add an appropriate catalyst-poison to thereaction mixture, e.g., thiophene or quinoline-sulphur. To enhance therate of the reaction, the temperature may be elevated in a range betweenroom temperature and the reflux temperature of the reaction mixture.

[0087] In the following paragraphs there are described different ways ofconverting compounds of formula (I) into each other following art-knownfunctional group transformation procedures. In order to simplify thestructural formulae of the compounds of formula (I), the substitutedpiperidine moiety will be represented by the symbol M hereinafter.

[0088] For instance, compounds of formula (I) wherein R¹ is C₁₋₄alkylsubstituted with hydroxy, said compounds being represented by formula(I-a), may be converted in the corresponding compounds of formula (I)wherein R¹ is C₁₋₄alkylcarbonyloxyC₁₋₄alkyl, said compounds beingrepresented by formula (I-b), according to art-known esterificationmethods such as, e.g. treatment with an acyl halide in the presence of abase to pick up the acid liberated during the reaction.

[0089] Also, compounds of formula (I-a) wherein R¹ is CH₂OH, saidcompounds being represented by formula (I-a-1), may be converted in thecorresponding compounds of formula (I) wherein R¹ is CHO, said compoundsbeing represented by formula (I-c), by oxidation with a suitable reagentsuch as, e.g. manganese(IV)oxide.

[0090] Further, compounds of formula (I) wherein R¹ contains a carboxylgroup, said compounds being represented by formula (I-d), may beconverted in the corresponding esters by art-known methods such as, e.g.treatment with an alcohol in the presence of an acid or base.

[0091] Conversely, compounds of formula (I-e) may be hydrolyzed intocompounds of formula (I-d), in the presence of an acid or a base.

[0092] The compounds of formula (I-c) may be converted into compounds offormula (I) wherein R¹ is a methoxycarbonylmethyl, said compounds beingrepresented by formula (I-f), by treatment with methyl methylthiomethylsulfoxide in the presence of benzyltrimethyl ammonium hydroxide in areaction-inert solvent, e.g. tetrahydrofuran.

[0093] Also, compounds of formula (I-c) may be converted into compoundsof formula (I-e) wherein X is a direct bond, said compounds beingrepresented by formula (I-e-1), by treatment with an alcohol, such as,e.g. methanol or ethanol, in the presence of acetic acid, MnO₂ and NaCN.

[0094] Compounds of formula (I) wherein Z² represents —C(═O)—CH₂—, saidcompounds being represented by formula (I-g), can be converted in thecorresponding alcohols by art-known reduction procedures such as, e.g.treatment with sodiumborohydride in a suitable solvent, e.g. methanol.

[0095] The starting materials and some of the intermediates are knowncompounds and are commercially available or may be prepared according toconventional reaction procedures generally known in the art. Forexample, a number of intermediates of formula (III), especially thosewherein Z is Z², are known compounds which may be prepared according toart-known methodologies described in EP-0,518,435-A, EP-0,518,434-A andWO-95/02600.

[0096] In the following paragraphs there are described several methodsof prepraring the intermediates employed in the foregoing preparations.

[0097] The intermediates of formula (II) may be prepared by O-alkylatingthe aromatic hydroxyl group of intermediate (VI) with an intermediate offormula (IV), wherein W¹ is a suitable leaving group such as, e.g. halo,methanesulfonyloxy or benzenesulfonyloxy, and subsequent conversion ofthe hydroxy group of intermediate (VII) into leaving group W, e.g. bytreating intermediate (VII) with methanesulfonyloxy chloride or ahalogenating reagent such as, e.g. POCl₃.

[0098] Said O-alkylation reaction can conveniently be carried out bymixing the reactants in a reaction-inert solvent such as, for example,methanol or N,N-dimethylformamide, and in the presence of an appropriatebase such as, e.g. sodium carbonate or sodium hydrogen carbonate,preferably at a temperature ranging between room temperature and thereflux temperature of the reaction mixture.

[0099] Also, intermediates of formula (II) wherein —A¹— isC₁₋₆alkanediyloxy, said intermediates being represented by compounds offormula (II-a), may be prepared by reacting an intermediate of formula(VIII) with an intermediate of formula (IX) in the presence of anappropriate base such as, e.g. potassium carbonate, and optionally inthe presence of a reaction-inert solvent such as, for example,N,N-dimethylformamide, acetonitrile or tetrahydrofuran. Subsequentconversion of the hydroxy group into a leaving group W, e.g. bytreatment with methanesulfonyloxy chloride or a halogenating reagentsuch as, e.g. POCl₃, yields intermediates of formula (II-a). It may beadvantageous to conduct said O-alkylation reaction at a temperatureranging between room temperature and reflux temperature.

[0100] In an embodiment, the present invention also provides for novelcompounds of formula (II), represented by compounds of formula (I-b)wherein radical —A^(1′)— represents C₁₋₆alkanediyl, C₁₋₆alkanediyloxy orC₁₋₆alkanediyloxyC₁₋₆alkanediyl and Q¹ represents all substituents Qother than unsubstituted phenyl.

[0101] Intermediates of formula (V) wherein —A^(1′)— representsC₁₋₆alkanediyl, C₁₋₆alkanediyloxy, C₁₋₆alkanediyloxyC₁₋₆alkanediyl, saidintermediates being represented by formula (V-a), may be prepared byreductive N-alkylation of an intermediate of formula (III) with anintermediate of formula (X). Optionally, intermediate (X) has aprotected hydroxyl group which can be deprotected using art-knownmethods subsequent to the reductive N-alkylation. In said intermediate(X), —A^(1″)— represents a direct bond, C₁₋₅alkanediyl,C₁₋₅alkanediyloxy or C₁₋₆alkanediyloxyC₁₋₅alkanediyl whereby the formylgroup is bonded on the C₁₋₅alkanediyl part. Said reductive N-alkylationmay be performed according to the hereinabove described procedure.

[0102] Intermediates of formula (III-a), defined as intermediates offormula (III) wherein Z is Z¹, may be prepared according to scheme I.

[0103] In scheme I, an intermediate of formula (XII) can be cyclized inan analogous way as an intermediate of formula (XI), giving an alcoholof formula (XIII) which can be oxidized following art-known oxidationmethods into a ketone of formula (XIV). An intermediate of formula (XVI)can be prepared by addition of a Grignard reagent (XV), wherein PG is asuitable protecting group, e.g. benzyl, to a ketone of formula (XIV) ina reaction-inert solvent, e.g. tetrahydrofuran. An intermediate offormula (III-a) can be prepared by dehydration of an intermediate (XVI)subsequently with catalytic hydrogenation of an intermediate (XVII).Said dehydration reaction can conveniently be conducted employingconventional dehydrating reagents, e.g. sulfuric acid, followingart-known methodologies. Said catalytic hydrogenation reaction can beconducted following art-known procedures, e.g. stirring in areaction-inert solvent, e.g. methanol, in the presence of a suitablecatalyst, e.g. palladium-on-carbon and in the presence of hydrogen,optionally the temperature may be elevated in a range between roomtemperature and the reflux temperature of the reaction mixture and, ifdesired, the pressure of the hydrogen gas may be raised.

[0104] Further, intermediates of formula (III-a) wherein R¹ is halo,said intermediates being represented by formula (III-a-1), can beprepared by halogenating intermediates of formula (XVIII), wherein PG isa protective group such as, e.g. C₁₋₆alkyl, and subsequent deprotection.For instance, when PG is C₁₋₆alkyl, PG may be removed by a carbonylationreaction with a C₁₋₄alkylchloroformate and subsequent hydrolysis with abase.

[0105] Said halogenation reaction can conveniently be conducted bytreating intermediates (XVIII) with a halogenating reagent such as, forexample, N-chlorosuccinimide or N-bromosuccinimide, in a reaction-inertsolvent such as, e.g. dichloromethane, optionally in the presence of aninitiator such as, e.g. dibenzoyl peroxide.

[0106] Also, the intermediates of formula (III) wherein Z is Z¹ and thedotted line is not a bond, said intermediates being represented bycompounds of formula (II-b), can generally be prepared by cyclizing anintermediate of formula (XI).

[0107] Said cyclization reaction is conveniently conducted by treatingan intermediate of formula (XI) with an appropriate acid, yielding anintermediate of formula (III-a). Appropriate acids are, for example,methanesulfonic acid or trifluoromethanesulfonic acid. It should benoted that only those intermediates of formula (III-a) wherein R¹ and R²are stable under the given reaction conditions can be prepared accordingto the above reaction procedure.

[0108] Compounds of formula (I) and some of the intermediates may haveone or more stereogenic centers in their structure, present in a R or aS configuration.

[0109] The compounds of formula (I) as prepared in the hereinabovedescribed processes may be synthesized as a mixture of stereoisomericforms, in particular in the form of racemic mixtures of enantiomerswhich can be separated from one another following art-known resolutionprocedures. The racemic compounds of formula (I) may be converted intothe corresponding diastereomeric salt forms by reaction with a suitablechiral acid. Said diastereomeric salt forms are subsequently separated,for example, by selective or fractional crystallization and theenantiomers are liberated therefrom by alkali. An alternative manner ofseparating the enantiomeric forms of the compounds of formula (I)involves liquid chromatography using a chiral stationary phase. Saidpure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, saidcompound will be synthesized by stereospecific methods of preparation.These methods will advantageously employ enantiomerically pure startingmaterials.

[0110] The compounds of formula (I), the N-oxide forms, thepharmaceutically acceptable addition salts and stereoisomeric formsthereof have valuable pharmacological properties in that they inhibit orreverse the effects of multidrug resistance, as can be evidenced by theresults obtained in the MDR in vitro test (Example C-1) and the MDR invivo test (Example C-2).

[0111] The term multidrug resistance (MDR) describes the phenomenon bywhich cells, in particular cancer cells, or pathogens become resistantto multiple drugs that may have little similarity in the structure ormechanism of action. The major cause of MDR is overexpression of amembrane-associated transporter, i.e. P-glycoprotein, which decreasesthe intracellular concentration of cytotoxicdrugs by binding the drugand actively pumping it out of the cell before it reaches a criticalcytotoxic concentration (Dalton W. S., Seminars in oncology, 20:66-69,1993).

[0112] Other resistance mechanisms include alterations in topoisomerase,glutathione S-transferase, nucleoside transport, thymidilate synthase,dihydrofolate reductase and metallothionein.

[0113] Further, the compounds of formula (I) are useful in inhibitingtransport of a chemotherapeutic agent through a membrane by amembrane-associated transporter, especially the membrane-associatedtransporter P-glycoprotein, and thereby maintaining effectiveness ofthis agent.

[0114] In view of their MDR inhibiting or reversing activity, thecompounds of formula (I) are suitable for use as a medicine, inparticular for decreasing, eliminating or reversing a developing orexisting resistance to chemotherapeutic drug therapy, or avoiding suchresistance from arising, by administration of a therapeuticallyeffective amount of a compound of formula (I). Diseases, disorders orconditions wherein treatment is hampered by multidrug resistance are,for example, neoplastic diseases caused by the growth of neoplasms (ortumors) such as, for example, haematological tumors (leukemias,lymphomas), renal carcinoma, ovarian, breast carcinoma, melanoma, tumorsin the colon and lungs and the like, and diseases such as, e.g.multidrug resistance forms of malaria, tuberculosis, leishmaniasis,amoebic dysentery and the like, caused by pathogens which acquiredresistance to pharmaceutical agents such as, e.g. chloroquine,pyrimethamine-sulfadoxime, mefloquine, halofantrine, isoniazid,streptomycin, rifampicin, pyrazinamide, nalidixic acid, ampicillin andthe like.

[0115] The compounds of formula (I) may conveniently be used incombination with a chemotherapeutic agent. The invention thus provides acombination comprising a composition as defined herein, together with atherapeutically active agent, in particular an anti-neoplastic agent.The combination may be administered separately, simultaneously,concurrently or consecutively by any of the routes described above, orthe combination may also be presented in the form of one pharmaceuticalformulation. Thus, a pharmaceutical product comprising (a) a compound offormula (I) and (b) a chemotherapeutic agent as defined hereinbefore, asa combined preparation for simultaneous, separate or sequential use inthe therapeutic or prophylactic treatment of warm-blooded animalssuffering from disorders or conditions wherein multidrug resistancehampers the treatment. Such a product may comprise a kit comprising acontainer containing a pharmaceutical composition of a compound offormula (I), and another container comprising a pharmaceuticalcomposition of the chemotherapeutic agent. The product with separatecompositions of the two active ingredients has the advantage thatappropriate amounts of each component, and timing and sequence ofadministration can be selected in function of the patient.

[0116] Suitable chemotherapeutic agents for use in the combinationsdefined above include are, for example, anti-neoplastic agents such as,e.g. adriamycine, daunorubicin, doxorubicin, vincristine, vinblastine,etoposide, taxol, taxotere, dactinomycin, mitoxantrone, mitomycin,trimetrexate and the like, for the treatment of neoplastic diseases andpharmaceutical agents such as, e.g. chloroquine,pyrimethaminesulfadoxime, mefloquine, halofantrine, isoniazid,streptomycin, nalidixic acid and ampicillin, for the treatment ofdiseases caused by pathogens which acquired resistance to multiplepharmaceutical agents.

[0117] When compounds of formula (I) are used in combination with achemotherapeutic agent, the dose of the chemotherapeutic agent may varyfrom the dose when used alone. Thus when compounds of formula (I) areused together with a chemotherapeutic agent the dose of the latter maybe the same or more commonly, lower, than the dose employed when thechemotherapeutic agent is used alone. Appropriate doses will be readilyappreciated by those skilled in the art.

[0118] In view of the above uses of the compounds of formula (I), itfollows that the present invention also provides a method of treatingwarm-blooded animals suffering from those diseases or conditions whereintreatment is hampered by multidrug resistance, said method comprisingthe systemic administration of a therapeutic amount of a compound offormula (I) effective in avoiding, inhibiting or reversing the effectsof multidrug resistance.

[0119] The present invention provides a method for the use of compoundsof formula (I) for decreasing, eliminating or reversing a developing orexisting resistance to anti-neoplastic drug therapy, or avoiding suchresistance from arising, by administration of a therapeuticallyeffective amount of a compound of formula (I).

[0120] Also, a method is provided for the use of compounds of formula(I) in the treatment of diseases or conditions caused by pathogens whichhave acquired resistance to pharmaceutical agents, said methodcomprising the systemic administration of a therapeutic amount of acompound of formula (I) effective in inhibiting or reversing multidrugresistance, and a pharmaceutical agent useful to treat those conditions.

[0121] For ease of administration, the subject compounds may beformulated into various pharmaceutical forms for administrationpurporses. To prepare the pharmaceutical compositions of this invention,an effective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally or by parenteral injection. For example, in preparing thecompositions in oral dosage form, any of the usual pharmaceutical mediamay be employed, such as, for example, water, glycols, oils, alcoholsand the like in the case of oral liquid preparations such assuspensions, syrups, elixirs and solutions; or solid carriers such asstarches, sugars, kaolin, lubricants, binders, disintegrating agents andthe like in the case of powders, pills, capsules and tablets. Because oftheir ease in administration, tablets and capsules represent the mostadvantageous oral dosage unit form, in which case solid pharmaceuticalcarriers are obviously employed. For parenteral compositions, thecarrier will usually comprise sterile water, at least in large part,though other ingredients, for example, to aid solubility, may beincluded. Injectable solutions, for example, may be prepared in whichthe carrier comprises saline solution, glucose solution or a mixture ofsaline and glucose solution. Injectable suspensions may also be preparedin which case appropriate liquid carriers, suspending agents and thelike may be employed. In the compositions suitable for percutaneousadministration, the carrier optionally comprises a penetration enhancingagent and/or a suitable wetting agent, optionally combined with suitableadditives of any nature in minor proportions, which additives do notcause a significant deleterious effect to the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of (I) due to theirincreased water solubility over the corresponding base form, areobviously more suitable in the preparation of aqueous compositions. Itis especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

[0122] The compositions may advantageously be presented in discrete doseunits, especially in unit dosage forms. A convenient unit doseformulation contains the active ingredient in an amount of from 0.1 to1000 mg, and in particular from 1 to 200 mg. The amount of a compound offormula (I) required as daily dose in treatment will vary not only withthe particular compound selected, but also with the route ofadministration, the nature of the condition being treated and the age,weight and condition of the patient and will ultimately be at thediscretion of the attendant physician. In general, however, a suitabledaily dose will be in the range of from about 0.1 to about 5000 mg perday, in particular from about 1 to 1000 mg per day, more particular fromabout 10 to 500 mg per day. A suitable daily dose for use in prophylaxiswill generally be in the same range.

[0123] The following examples are provided for purposes of illustration,not limitation.

[0124] Experimental Part

[0125] A. Preparation of the Intermediates.

[0126] Hereinafter “THF” means tetrahydrofuran, “DIPE” meansdiisopropylether, “DCM” means dichloromethane, “DMF” meansN,N-dimethylformamide and “ACN” means acetonitrile.

EXAMPLE A.1

[0127] a) 4-Hydroxybenzeneethanol (103.5 g) was stirred in ethanol (1.5l), at room temperature. A solution of potassium hydroxide (84 g) inethanol (1.5 l) was added dropwise, over a 1 hour period.2-(Chloromethyl)quinoline monohydrochloride was added portionwise over a25-minutes period. The reaction mixture was stirred and refluxed for 12hours. The reaction mixture was poured out into water (5 l) and thismixture was stirred vigorously. The precipitate was filtered off, andwashed with water (2 l). Toluene was added and azeotroped on the rotaryevaporator. The residue was dried, yielding 187 g (89%) of4-(2-quinolinylmethoxy)benzeneethanol (intermediate 1, mp. 144.8° C.).

[0128] b) A mixture of intermediate 1 (2.79 g) and N,N-diethylethanamine(1.2 g) in DCM (50 ml) was stirred on an ice bath. Methanesulfonylchloride (1.26 g) was added dropwise at a temperature below 110° C. Themixture was brought to room temperature and then stirred for 1 hour.Water was added and the mixture was extracted with DCM. The organiclayer was washed with water, dried, filtered and evaporated, yielding3.8 g (100%) of 4-(2-quinolinylmethoxy)benzeneethanolmethanesulfonate(ester)(interm. 2). In a similar way,3-(2-quinolinylmethoxy)benzeneethanol methanesulfonate(ester)(intermediate 3) and 4-[(6-methyl-2-quinolinyl)methoxy]benzeneethanolmethanesulfonate(ester) (intermediate 4) were synthesized.

EXAMPLE A.2

[0129] a) 3-(2-Quinolinyl-methoxy)phenol (12.5 g), potassium carbonate(10.4 g) and 1,3-dioxolan-2-one (44 g) were stirred on an oil bath at100° C. for 2 hours. The mixture was cooled, poured into water andextracted with DCM. The organic layer was dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel (eluent: CH₂Cl₂/CH₃OH 97/3). The pure fractions werecollected and evaporated. The residue was stirred up in DIPE. Theprecipitate was filtered off and dried, yielding 11.9 g (80.6%) of2-[3-(2-quinolinyl-methoxy)phenoxy]ethanol (intermediate 5).

[0130] b) A mixture of intermediate 5 (2.95 g) and N,N-diethylethanamine(1.2 g) in DCM (50 ml) was stirred on an ice bath. Methanesulfonylchloride (1.26 g) was added dropwise at a temperature below 5° C. Themixture was brought to room temperature and then stirred for 1 hour.Water was added and the mixture was stirred. The mixture was separatedand the aqueous layer was extracted with DCM. The combined organiclayers were washed with water, dried, filtered and evaporated, yielding4.5 g (100%) of 2-[3-(2-quinolinyl-methoxy)phenoxy]ethanolmethanesulfonate(ester) (intermediate 6). In a similar way,2-[4-(2-quinolinylmethoxy)phenoxy]ethanol methanesulfonate(ester)(intermediate 7) was synthesized.

EXAMPLE A.3

[0131] A mixture of 3,5-dimethoxy-4-hydroxybenzaldehyde (8 g) and6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine (9g) in methanol (250 ml) and thiophene (4%, 3 ml) was hydrogenated atroom temperature with palladium on activated carbon (10%, 2 g) as acatalyst. After uptake of hydrogen (1 equivalent), the catalyst wasfiltered off and the filtrate was evaporated. The residue was purifiedby column chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 95/5).The pure fractions were collected and evaporated, yielding 9.5 g (65%)of4-[4-(5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene)-1-piperidinyl]-2,6-dimethoxyphenol(intermediate 8).

[0132] In a similar way,6,11-dihydro-11-[1-[(4-hydroxy-3,5-dimethoxyphenyl)methyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol(intermediate 9) was synthesized.

EXAMPLE A.4

[0133] A mixture ofα-[1-(phenylmethyl)-1H-imidazol-2-yl]-4-piperidinemethanol (5.4 g) intrifluoromethanesulfonic acid (25 ml) was stirred overnight at 100° C.The reaction mixture was cooled, poured out onto ice, then alkalizedwith NaOH and this mixture was extracted with DCM. The separated organiclayer was dried, filtered and the solvent was evaporated. The residuewas purified over silica gel on a glass filter (eluent:CH₂Cl₂/(CH₃OH/NH₃) 95/5, upgrading to 90/10). The pure fractions werecollected and the solvent was evaporated, yielding 2.5 g (50%) of5,10-dihydro-10-(4-piperidinyl)-imidazo[1,2-b]isoquinoline (intermediate10).

EXAMPLE A.5

[0134] a)6,11-Dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine(28 g) was stirred in DCM (500 ml), until complete dissolution.Dibenzoyl peroxide (0.1 g) was added. N-chlorosuccinimide (13.4 g) wasadded portionwise and the resulting reaction mixture was stirredovernight at room temperature, then for 2 hours at reflux temperature.The solvent was evaporated. The residue was purified by columnchromatography over silica gel (eluent : CH₂Cl₂/(CH₃OH/NH₃) 97/3,upgrading to 95/5). The pure fractions were collected and the solventwas evaporated. The residue was crystallized from ACN. The precipitatewas filtered off and dried, yielding 23.3 g (74%) of3-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-imidazo-[2,1-b][3]benzazepine(intermediate 11).

[0135] b) A mixture of intermediate 11 (31.4 g) andN,N-diethylethanamine (20.2 g) in toluene (11) was stirred and refluxed.Ethyl chloroformate (65.1 g) was added dropwise. The reaction mixturewas stirred and refluxed for 90 minutes. The mixture was cooled. Waterand K₂CO₃ were added and the layers were separated. The aqueous layerwas extracted with toluene. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue wascrystallized from DIPE. The precipitate was filtered off and dried,yielding 32.4 g (87%) of ethyl4-(3-chloro-5,6-dihydro-11H-imidazo[2,1-b][3]benzazepin-11-ylidene)-1-piperidinecarboxylate(intermediate 12).

[0136] c) A mixture of intermediate 12 (30.4 g) and potassium hydroxide(46 g) in isopropanol (370 ml) was stirred and refluxed for 6 hours. Thesolvent was evaporated. The residue was taken up in water and extractedwith DCM. The organic layer was separated, dried (MgSO₄), filtered andthe solvent was evaporated. The residue was crystallized from ACN. Theprecipitate was filtered off and dried, yielding 1.65 g (90%) of3-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-imidazo[2,1-b][3]benzazepine(intermediate 13).

[0137] B. Preparation of the Final Products.

EXAMPLE B.1

[0138] A mixture of intermediate 2 (8.6 g), intermediate 13 (6 g) andsodium hydrogen carbonate (2.2 g) in ethanol (300 ml) was stirred andrefluxed for 48 hours. The solvent was evaporated and the residue wastaken up in water and DCM. The layers were separated and the aqueouslayer was extracted with DCM. The organic layer was separated, dried(MgSO₄), filtered and the solvent was evaporated. The residue waspurified on a glass filter over silica gel (eluent: CH₂Cl₂/(CH₃OH/NH₃)95/5). The pure fractions were collected and the solvent was evaporated.The residue was crystallized from ethanol. The precipitate was filteredoff and dried, yielding 8.21 g (73%) of3-chloro-6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine(compound 13).

[0139] In a similar way,6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol(compound 2) was synthesized.

EXAMPLE B.2

[0140] 2-(Chloromethyl)quinoline monohydrochloride (4.06 g) was taken upin water, alkalized with K₂CO₃ and extracted with DCM. The organic layerwas dried (MgSO₄), filtered and evaporated, yielding2-(chloromethyl)quinoline. Sodium hydride (0.7 g) was added at roomtemperature to a solution of intermediate 8 (6.5 g) in DMF (350 ml) andthe mixture was stirred for 30 minutes. 2-(Chloromethyl)quinolinedissolved in DMF was added and the mixture was stirred at 50° C. for 3hours. The mixture was evaporated, the residue was taken up in water andextracted with DCM. The organic layer was dried (MgSO₄), filtered andevaporated. The residue was crystallized from ACN, the precipitate wasfiltered off, yielding 5.52 g (64%) of11-[1-[[3,5-dimethoxy-4-(2-quinolinylmethoxy)-phenyl]methyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine(compound 32, mp. 214.8° C.).

EXAMPLE B.3

[0141] A mixture of compound 2 (5.56 g) and N,N-diethylethanamine (1.2g) in DCM (100 ml) was stirred at room temperature till completedissolution. A solution of acetyl chloride (0.86 g) in DCM was addeddropwise. The mixture was stirred at room temperature for 1 hour. K₂CO₃(2 g) and water were added and the mixture was separated into itslayers. The aqueous layer was extracted with DCM. The combined organiclayer was dried (MgSO₄), filtered and the solvent was evaporated. Theresidue was crystallized from ACN. The precipitate was filtered off anddried, yielding 3.95 g (66%) of[5,6-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-11H-imidazo[2,1-b][3]benzazepine-3-yl]methanol acetate(ester) (compound 3).

EXAMPLE B.4

[0142] Compound 2 (206 g) was dissolved in DCM (11 l) under continuousstirring. Manganese dioxide (450 g) was added in 100-g portions and theresulting reaction mixture was stirred for 1 hour. The mixture wasfiltered over dicalite and the filtrate was evaporated. The residue wasstirred in ACN, filtered off and dried, yielding 170 g (83%) of6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxaldehyde(compound 4, mp. 193.5° C.).

EXAMPLE B.5

[0143] A mixture of compound 4 (8.32 g) and methyl methylthiomethylsulfoxide (MMTS) (4.5 g) in THF (100 ml) and benzyltrimethyl ammoniumhydroxide (40% in methanol; 20 ml) was stirred and refluxed overnight.The solvent was evaporated. The residue was taken up in water andextracted with DCM. The organic layer was separated, dried (MgSO₄),filtered and the solvent was evaporated. Toluene was added twice andevaporated again. The residue was taken up in methanol (50 ml). HCl gaswas bubbled through the mixture, cooled on an ice bath, for 30 minutes.The mixture was stirred overnight. The solvent was evaporated. Theresidue was taken up in water, alkalized with K₂CO₃ and extracted withDCM. The organic layer was separated, dried, filtered and the solventwas evaporated. The residue was purified over silica gel on a glassfilter (eluent: CH₂Cl₂/CH₃OH 95/5). The pure fractions were collectedand the solvent was evaporated. The residue was crystallized from ACN.The precipitate was filtered off and dried, yielding 2.7 g (30%) ofmethyl6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-acetate(compound 5).

EXAMPLE B.6

[0144] A mixture of compound 4 (164 g), sodium cyanate (80 g) andmanganese dioxide (500 g) in methanol (5.5 l) was stirred at roomtemperature. Ethanoic acid (122 g) was added dropwise and the resultingreaction mixture was stirred and refluxed overnight. The reactionmixture was filtered over dicalite, and the filter residue was rinsedwith CH₃OH/CH₂Cl₂. The filtrate was evaporated. The residue waspartitioned between DCM and aqueous K₂CO₃ solution. The organic layerwas separated, dried (MgSO₄), filtered and the solvent was evaporated.The residue was crystallized from ACN. The precipitate was filtered offand dried, yielding 152 g (87%) of methyl6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-SH-imidazo[2,1-b][3]-benzazepine-3-carboxylate(compound 6, mp. 179.3° C.).

EXAMPLE B.7

[0145] A mixture of compound 6 (37 g) in NaOH (1N, 150 ml), THF (500 ml)and water (500 ml) was stirred at room temperature overnight. Theorganic solvent was evaporated. The aqueous concentrate was washed withDCM and acidified with HCl (1N, 150 ml). The solvent was evaporated. Theresidue was stirred in water, filtered off and dried, yielding 32 g(84%) of6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylicacid (compound 7, mp. 174.2° C.).

EXAMPLE B.8

[0146] A mixture of compound 27 (3.5 g) in methanol (100 ml) was stirredat room temperature. Sodium borohydride (0.34 g) was added portionwiseand the mixture was stirred at room temperature for 2 hours. The mixturewas evaporated, the residue was taken up in water and extracted withCH₂Cl₂/C₂H₅OH. The organic layer was dried, filtered and evaporated. Theresidue was crystallized from ACN. The precipitate was filtered off anddried, yielding 2.39 g (68%) of(±)-6,10-dihydro-10-[1-[2-[4-(2-quinolinylmethoxy)-phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[1,2-a]thieno[3,2-d]azepin-6-ol(compound 28, mp. 242.1° C.).

EXAMPLE B.9

[0147] A mixture of compound 7 (3 g) and N,N-dimethyl-4-pyridinamine(1.22 g) in DCM (100 ml) was stirred till complete dissolution.1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.8 g) wasadded portionwise and the mixture was stirred at room temperature for 15minutes. A solution of benzenemethanol (0.54 g) in DCM was added. Themixture was stirred at room temperature overnight. The solvent wasevaporated. The residue was purified over silica gel on a glass filter(eluent: CH₂Cl₂/CH₃OH 97/3 to 95/5). The pure fractions were collectedand the solvent was evaporated. The residue was crystallized from ACN.The precipitate was filtered off and dried, yielding 2.06 g (62%) ofphenylmethyl6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate(compound 9).

[0148] Ina similar way, but replacing the alcohol by ammonia ordimethylamine, compound 55 (compound) and compound 56 (compound )respectively were synthesized.

EXAMPLE B.10

[0149] A mixture of compound 2 (27.8 g) in DCM (500 ml) was stirred atroom temperature till complete dissolution. Dibenzoylperoxide (a fewcrystals) was added portionwise, then a solution of N-chlorosuccinimide(7 g) in DCM was added dropwise at room temperature and the mixture wasstirred at room temperature for 18 hours. The solvent was evaporated andthe residue was purified by column chromatography over silica gel(eluent : CH₂Cl₂/(CH₃OH/NH₃) 96/4 to 92/8). The pure fractions werecollected and the solvent was evaporated. The residue was purifiedfurther by HPLC over silica gel (eluent: CH₂Cl₂/CH₃OH 96/4 to 50/50).The pure fractions were collected and the solvent was evaporated. Thefirst fraction was crystallized from CH₃OH, yielding 8.84 g (30%) ofcompound 59. The second fraction was crystallized from ACN, yielding1.91 g (6%) of compound 58.

EXAMPLE B.1

[0150] A mixture of compound 6 (5.55 g) and methyl(triphenylphosphoranylidene)acetate (3.34 g) in toluene (300 ml) wasstirred and refluxed overnight. The solvent was evaporated. The residuewas purified over silica gel on a glass filter (eluent: CH₂Cl₂/CH₃OH95/5). The pure fractions were collected and the solvent was evaporated.The residue was crystallized from ACN. The precipitate was filtered off,dried, recrystallized from ACN and purified by HPLC Hypersil RP-18 3 μM(eluent: (NH₄OAc/0.5% in H₂O)/CH₃OH/CH₃CN 70/15/15, 0/50/50 to 0/0/100).The pure fractions were collected, evaporated till aqueous and extractedwith DCM. The organic layer was separated, dried, filtered and thesolvent was evaporated. The residue was crystallized from ACN. Theprecipitate was filtered off and dried, yielding 0.45 g (7%) of compound62.

EXAMPLE B.12

[0151] A mixture of compound 71 (4.5 g) in CH₃OH (350 ml) was stirred onan ice bath. NaBH₄ (0.38 g) was added portionwise at 0° C. over a periodof 15 minutes. The mixture was stirred at room temperature for 1 hourand then decomposed with water. The organic solvent was evaporated. Theaqueous concentrate was extracted with DCM. The combined organic layerwas dried, filtered and the solvent was evaporated. The residue waspurified over silica gel on a glass filter (eluent: CH₂Cl₂/CH₃OH 95/5).The pure fractions were collected and the solvent was evaporated. Theresidue was crystallized from ACN. The precipitate was filtered off anddried, yielding: 3.5 g (78%) of compound 73.

EXAMPLE B.13

[0152] A mixture of methyl6,11-dihydro-4-piperidinylidene-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate(3.23 g) and N,N-dimethylpyridinamine (2.4 g) in DCM (200 ml) wasstirred at room temperature.1-(3-Dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (3.83 g)was added portionwise. The mixture was stirred at room temperature for 1hour. 4-(2-Quinolinylmethoxy) benzoic acid (2.8 g) dissolved in DCM wasadded dropwise. The mixture was stirred at room temperature overnight.Water was added. The mixture was separated into its layers. The aqueouslayer was extracted with DCM. The combined organic layer was dried,filtered and the solvent was evaporated. The residue was purified bycolumn chromatography over silica gel (eluent: CH₂Cl₂/CH₃OH 95/5). Thepure fractions were collected and the solvent was evaporated. Theresidue was dissolved in CH₃OH and converted into the (E)-2-butenedioicacid salt (1:1). The precipitate was filtered off and dried, yielding3.36 g (48%) of compound 72.

EXAMPLE B.14

[0153] A mixture of compound 71 (4.5 g) and hydroxylamine (1.1 g) inpyridine (50 ml) was stirred and refluxed for 90 minutes. The solventwas evaporated. The residue was stirred in H₂O/CH₂Cl₂. K₂CO₃ (2 g) wasadded. The mixture was separated into its layers. The aqueous layer wasextracted with DCM. The combined organic layer was dried, filtered andthe solvent was evaporated. The residue was purified over silica gel ona glass filter (eluent: CH₂Cl₂/CH₃OH 95/5). The pure fractions werecollected and the solvent was evaporated. The residue was crystallizedfrom ACN. The precipitate was filtered off and dried, yielding 1.21 g(26%) of compound 74.

EXAMPLE B.15

[0154] A mixture of 4-phenoxy benzaldehyde (2 g) and methyl6,11-dihydro-4-piperidinylidene-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate(3.23 g) in methanol (150 ml) was hydrogenated at room temperatureovernight with Pd/C (10%, 1 g) as a catalyst in the presence of athiophene solution (1 ml). After uptake of hydrogen (1 equivalent), thecatalyst was filtered off and the filtrate was evaporated. The residuewas purified over silica gel on a glass filter (eluent : CH₂Cl₂/CH₃OH97/3 to 95/5). The pure fractions were collected and the solvent wasevaporated. The residue was crystallized from CH₃OH. The precipitate wasfiltered off and dried, yielding: 2.86 g (57%) of compound 90.

EXAMPLE B.16

[0155] A mixture of diisopropanolamine (1.13 g) in THF was stirred undernitrogen at −78° C. N-Butillithium (2.5 M in hexanes, 4.3 ml) was addedportionwise at −70° C. and the mixture was stirred for 15 minutes.1-(Diethoxymethyl)-1H-imidazole (1.81 g) dissolved in THF was addeddropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour.Compound 4 (5.54 g) dissolved in THF was added dropwise at −70° C. andthe mixture was stirred at −70° C. for 1 hour. The mixture was broughttill room temperature and it was stirred at room temperature overnight.Acetic acid (5 ml) was added and the mixture was stirred at roomtemperature for 20 minutes. K₂CO₃ (5 g) was added and the mixture wasevaporated. The residue was taken up in water and DCM and the layerswere separated. The aqueous layer was extracted with DCM. The combinedorganic layers were dried, filtered off and the solvent was evaporated,yielding 6.1 g (97%) of6,11-dihydro-α-(1H-imidazol-2-yl)-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol(compound 46).

[0156] Tables F-1 to F-6 list the compounds that were prepared accordingto one of the above Examples and Table F-7 lists both the experimental(column heading “exp.”) and theoretical (column heading “theor.”)elemental analysis values for carbon, hydrogen and nitrogen of thecompounds as prepared in the experimental part hereinabove. TABLE F-1

Co. Ex. Phys. Data No. No. A¹ R¹ R² —A—B— (mp. in ° C.) 14 B.1 —(CH₂)₂—H —CH₃ —CH═CH—N(CH₃)— mp. 150 15 B.1 —CH₂— H H —CH═CH—N(CH₃)— mp. 199.816 B.1 —(CH₂)₂— H H —CH═CH—N(CH₃)— mp. 179.5 17 B.1 —(CH₂)₂— H H—CH═CH—CF═CH— mp. 190.2 18 B.1 —O(CH₂)₂— H H —CH═CH—N(CH₃)— mp. 174.4 19B.1 —O(CH₂)₂— H H —CH═CH—CF═CH— mp. 136.0 37 B.1 —COCH₂— H H—CH═CH—N(CH₃)— mp. 220 38 B.12 —OCH₂CHOHCH₂— H H —CH═CH—N(CH₃)— mp.186.4 39 B.1 —(CH₂)₂— CH₂OH H —CH═CH—C(OCH₃)═CH— mp. 106.8

[0157] TABLE F-2

Co. Ex. Phys. Data No. No. A¹ R¹ R² (mp. in ° C.) 1 B.1 —(CH₂)₂— H H mp.200.1 2 B.1 —(CH₂)₂— —CH₂OH H mp. 220.1 3 B.3 —(CH₂)₂— —CH₂OCOCH₃ H — 4B.4 —(CH₂)₂— —CHO H mp. 193.5 5 B.5 —(CH₂)₂— —CH₂COOCH₃ H — 6 B.6—(CH₂)₂— —COOCH₃ H mp. 179.3 40 B.6 —(CH₂)₂— —COOCH₃ H mp. 142.6; •HCl(1:1)•H₂O(1:3) 41 B.6 —(CH₂)₂— —COOCH₃ H mp. 180.6; •HCl (1:2)•H₂O(1:1)42 B.6 —(CH₂)₂— —COOCH₃ H mp. 161.8; •(Z)-2-butene- dioate(1:1) 43 B.6—(CH₂)₂— —COOCH₃ H mp. 166.0; •ethanedioate (1:1) 44 B.6 —(CH₂)₂——COOCH₃ H •hydroxybutane- dioate 45 B.6 —(CH₂)₂— —COOCH₃ H mp. 204.1;•HCl (1:3) 7 B.7 —(CH₂)₂— —COOH H mp. 174.2 8 B.1 —(CH₂)₂— —CH₂OH —CH₂OHmp. 183.3; •hemihydrate 9 B.9 —(CH₂)₂— COOCH₂C₆H₅ H — 10 B.4 —(CH₂)₂——CHO —CHO — 11 B.6 —(CH₂)₂— —COOCH₃ —COOCH₃ — 12 B.6 —(CH₂)₂— —COOC₂H₅ H— 13 B.1 —(CH₂)₂— Cl H — 20 B.1 —O(CH₂)₂— H H mp. 138.2 46 B.16 —(CH₂)₂—

H — 47 B.4 —(CH₂)₂—

H mp. 222.6 48 B.9 —(CH₂)₂— —COOC₁₀H₂₁ H — 49 B.9 —(CH₂)₂— —COOC₁₂H₂₅ H— 50 B.9 —(CH₂)₂—

H — 51 B.9 —(CH₂)₂—

H — 52 B.9 —(CH₂)₂—

H — 53 B.9 —(CH₂)₂— —COO(CH₂)₂OC₂H₅ H — 54 B.9 —(CH₂)₂—

H — 55 B.9 —(CH₂)₂— —CONH₂ H — 56 B.9 —(CH₂)₂— —CON(CH₃)₂ H — 57 B.10—(CH₂)₂— —CH₂OH Cl mp. 211.3 58 B.10 —(CH₂)₂— Cl Cl mp. 191.1 59 B.10—(CH₂)₂— Cl —CH₂OH — 60 B.4 —(CH₂)₂— Cl —CHO — 61 B.6 —(CH₂)₂— Cl—COOC₂H₅ mp. 173.8 62 B.11 —(CH₂)₂— —CH═CH—COOCH₃ H mp. 172.3 63 B.4—(CH₂)₂— —CHO Cl mp. 208.4 64 B.1 —(CH₂)₂— H —CH₂OH mp. 149.0•(E)-2-butenedioate (1:2) 65 B.9 —(CH₂)₂— —COO(CH₂)₃CH₃ mp. 130.3 66 B.1—(CH₂)₂— H —CH₂OH — 67 B.4 —(CH₂)₂— H —CHO mp. 168.9 68 B.6 —(CH₂)₂— H—COOCH₃ mp. 200; 69 B.6 —(CH₂)₂— —COOCH₃ H mp. 200; •(E)-2-butenedioate(2:3) 70 B.1 —(CH₂)₂— —COOCH₃ H mp. 204.3 71 B.1 —COCH₂— —COOCH₃ H mp.152.3 72 B.13 —CO— —COOCH₃ H mp. 139.7; •(E)-2-butenedioate (1:1) 73B.12 —CH(OH)—CH₂— —COOCH₃ H mp. 154.9 74 B.14 —C(═NOH)—CH₂ —COOCH₃ H mp.186.5 75 B.1 —(CH₂)₃— —COOCH₃ H mp. 156.7 76 B.6 —(CH₂)₂— —COOCH₃ Cl —77 B.9 —(CH₂)₂— —COOCH(CH₃)₂ H mp. 165.9 102 B.2 —CO(CH₂)₃— —CH₂OH H mp.191.0

[0158] TABLE F-3

Co. Ex. Physical data No. No. A¹ —A—B— Z (mp. in ° C.) 21 B.1 —O(CH₂)₂——CH═CH—N(CH₃)— —(CH₂)₂— mp. 125.4 22 B.1 —O(CH₂)₂— —CH═CH—CF═CH——(CH₂)₂— mp. 135.6 mp. 180; 23 B.1 —(CH₂)₂— —CH═CH—CF═CH— —(CH₂)₂—•(cyclohexylsulfamate (1:2) salt 24 B.1 —(CH₂)₂— —CH═CH—N(CH₃)— —(CH₂)₂—mp. 127.7 25 B.1 —(CH₂)₂— —CH═CH—S— —CO—(CH₂)*— mp. 159.9 26 B.1—(CH₂)₂— —CH═CH—CH═CH— —O—(CH₂)*— mp. 176 27 B.1 —O(CH₂)₂— —CH═CH—CH═CH——O—(CH₂)*— mp. 189.8

[0159] TABLE F-4

Co. Ex. Physical data No. No. R^(a) A¹ ═ —A—B— Z (mp. in ° C.) 26 B.1 H—O(CH₂)₂— double —CH═CH—S— —CO—(CH₂)*— mp. 190.5;** 27 B.1 H —(CH₂)₂—double —CH═CH—S— —CO—(CH₂)*— mp. 201.4 28 B.7 H —(CH₂)₂— double—CH═CH—S— —CHOH—(CH₂)*— mp. 242.1 29 B.1 H —(CH₂)₂— double—CH═CH—N(CH₃)— —CO—(CH₂)*— mp. 200; ** 30 B.1 H —(CH₂)₂— double—CH═CH—N(CH₃)— —CO—(CH₂)*— mp. 175.4 31 B.1 —CH₃ —(CH₂)₂— double—CH═CH—N(CH₃)— —(CH₂)₂— mp. 188.1 32 B.1 H —(CH₂)₂— double —CH═CH—CH═CH——(CH₂)*—O— mp.170.7

[0160] TABLE F-5

Co. Ex. No. No. A¹ R¹ R⁴ ═ Z Physical 32 B.2 —CH₂— H —OCH₃ double—(CH₂)₂— mp. 214.8° C. 33 B.2 —CH₂— —CH₂OH —OCH₃ double —(CH₂)₂— mp.220.8° C. 34 B.4 —CH₂— —CHO —OCH₃ double —(CH₂)₂— mp. 154° C. 35 B.6—CH₂— —COOCH₃ —OCH₃ double —(CH₂)₂— mp. 144.2° C. 36 B.1 —(CH₂)₂ H Hsingle —CH₂— mp. 169.2° C. 81 B.1 —(CH₂)₂ —CH₂OH H single —(CH₂)₂— mp.179.3° C. 82 B.4 —(CH₂)₂ —CHO H single —(CH₂)₂— mp. 177.8° C. 83 B.6—(CH₂)₂ —COOCH₃ H single —(CH₂)₂— mp. 158.3° C. 84 B.1 —(CH₂)₂ H Hdouble —CH═CH— mp. 160.5° C. 85 B.2 —CH₂— —COOCH₃ Cl double —(CH₂)₂— mp.164.0° C. 86 B13 —CO— —COOCH₃ —CH₃ double —(CH₂)₂— mp. 131.2° C.

[0161] TABLE F-6

Co. Ex. No. No. Q—A² —A¹— Physical data 87 B.1

—CH₂CH₂— — 88 B.1 phenylmethyl —CH₂CH₂— — 89 B.1 2-pyridinylmethyl—CH₂CH₂— — 90 B15 phenyl —Ch₂— — 91 B.1

—CH₂CH₂— — 92 B.1

—CH₂CH₂— — 93 B.1 3,5-bis(trifluromethyl)phenylmethyl —CH₂CH₂— — 94 B.1

—CH₂CH₂— mp. 190.6° C. 95 B.1 6-chloro-2-pyridinyl —CH₂CH₂— mp. 139.1°C. 96 B.1 4-chlorophenylmethyl —CH₂CH₂— mp.171.2° C. 97 B.14-methoxyphenylmethyl —CH₂CH₂— mp. 174.8° C. 98 B.1

—CH₂CH₂— mp. 193.5° C. •(E)-2-butenedioate 99 B.13,5-diflurorophenylmethyl —CH₂CH₂— mp. 117.2° C. 100 B.15 phenyl—CH₂CH₂— mp. 132.3° C. 101 B.1 2-quinobnylmethyl —CH₂O(CH₂)₂— mp. 125.0103 B.1 3,5-dimethylphenylmethyl —CH₂CH₂— mp. 123.1

[0162] TABLE F-7 Comp. Carbon Hydrogen Nitrogen No. Exp. Theor. Exp.Theor. Exp. Theor. 115529 3 76.00 76.23 6.42 6.40 9.30 9.36 116085 575.28 76.23 6.35 6.40 9.18 9.36 116304 9 78.08 78.16 5.97 6.10 8.44 8.48115775 11 72.77 72.88 5.76 5.96 8.71 8.72 115999 12 76.12 76.23 6.336.40 9.41 9.36 115528 13 74.81 74.92 5.78 5.93 9.88 9.98 120646 76 72.6272.08 6.09 5.89 8.84 8.85 125029 87 78.24 78.19 6.31 6.39 6.85 7.20125242 88 76.32 76.52 6.63 6.61 7.73 7.87 125449 89 74.02 74.13 6.456.41 10.50 10.48 125546 90 76.22 76.02 6.35 6.18 8.35 8.31 125637 9178.85 78.19 6.42 6.39 7.10 7.20 125640 92 77.57 76.76 6.86 6.81 7.627.67 125683 93 65.05 64.57 5.14 4.97 6.14 6.27

[0163] C. Pharmacological Examples

EXAMPLE C.1

[0164] The in vitro effectiveness of a compound of formula (I) as a MDRmodulator was assessed using a human multidrug resistant cancer cellline (Park J. -G. et al., J. Natl. Cancer Inst., 86:700-705 (1994) andHill B. T. et al., Cancer Chemother. Pharmacol., 33:317-324 (1994)).Briefly, the cell growth of K562/C 1000, a human multidrug resistantcancer cell line, was measured in the presence of a full range ofconcentrations (ranging from 10-12 to 10⁻⁵ M) of a classic cytostatic,e.g. vinblastine. The IC₅₀(cytostatic), i.e. the concentration of thecytostatic needed to reduce cell growth by 50%, was measured. Also, thegrowth of K562/C1000 was measured in the presence of a full range ofconcentrations of a classic cytostatic and a fixed concentration (10⁻⁶M) of a MDR modulating compound, yielding IC_(50(cytostatic/compound)).The sensitization ratio ‘SR’ is determined as the ratio ofIC_(50(cytostatic)) over IC_(50(cytostatic/compound)). Compounds1,3,4,6,9, 11-13, 18,20,27,30-36,47,45,58,61-63,65,67,69,70, 73, 74, 75,77, 82, 84, 87-89 and 91-101 as listed in Tables F-1 to F-6 have a SRvalue greater or equal than 5. Compounds 2, 5, 8, 14, 15, 19, 19, 22,23-25, 26, 29, 33, 37, 38, 48, 52, 55-57, 64, 68, 71, 76, 78, 79, 80 and85 as listed in Tables F-1 to F-6 have a SR value between 1 and 5.

EXAMPLE C.2

[0165] The potential of compounds of formula (I) to reverse multidrugresistance can be demonstrated by the ability of compounds of formula(I) to reverse the adriamycine resistance in the P388/ADR (adriamycineresistance cell line) murine leukemia in vivo.

[0166] Male B6D2F1 mice (18-21 g) were injected intraperitoneally with1×10⁵ P388/ADR cells at day 0. Daily intraperitoneal treatment withadriamycine, a test compound of formula (I) or a combination of both wasinstalled from day 1 until day 10. Control animals received the vehicle(15% 4-OH-propyl-p-cyclodextrine in saline). Each group consisted of 8animals. Adriamycine was dosed at a concentration of 1.25 mg/kg bodyweight, half the maximal tolerable dose of adriamycine in this treatmentschedule. The test compound was dosed at 20, 10, 5, 2.5, 1.25 and 0.63mg/kg either as single treatment or combined with adriamycine.

[0167] Survival of the animals was recorded each day and expressed as apercentage of the median survival in the treated groups compared to themedian survival in the control group, the latter to be said to be 100%.

[0168] Table C-1 lists the effect of compound 6 and adriamycine on thesurvival of mice injected with P388/ADR leukemia.

[0169] doses of compound 6 and adriamycine are expressed as mg/kg bodyweight.

[0170] the column “Suvival Days” give the median day of death afterinoculation of 1×10⁵ P388/ADR cells at day 0, with the minimum andmaximum number of days shown in parantheses

[0171] the column “MST % ” shows the median percentage of the treatedgroups compared to the median survival in the control group, the latterbe said to be 100%

[0172] column “% Change vs. ADR” give the difference in MST % of thedifferent groups compared to the MST % in the adriamycine-monotherapygroup. Table C-1 Survival Days Compound 6 Adriamycine med(min- % Changevs. (mg/kg) (mg/kg) max) MST % ADR 0 0   11(10-14) 100 −18 0 1.25  13(12-15) 118 0 20 0   11(10-14) 100 −18 10 0 10.5(10-13) 95 −23 5 0  11(10-13) 100 −18 2.5 0 10.5(10-12) 95 −23 1.25 0 11.5(10-16) 105 −130.63 0   11(10-12) 100 −18 20 1.25 15.5(14-17) 141 23 10 1.25  15(14-28) 136 18 5 1.25 14.5(11-16) 132 14 2.5 1.25 14.5(10-20) 132 141.25 1.25   15(14-17) 136 18 0.63 1.25 14.5(14->30) 132 14

[0173] Table C-1 illustrated that the group treated with a combinationof compound 6 and adriamycine have a Median Survival Time (MST) which is14 to 23% longer than the adriamycine mono-therapy group.

[0174] D. Composition Examples

[0175] The following formulations exemplify typical pharmaceuticalcompositions in dosage unit form suitable for systemic or topicaladministration to warm-blooded animals in accordance with the presentinvention.

[0176] “Active ingredient” (A.I.) as used throughout these examplesrelates to a compound of formula (I), a N-oxide form, a pharmaceuticallyacceptable acid or base addition salt or a stereochemically isomericform thereof.

EXAMPLE D.1 Oral Solutions

[0177] 9 g of methyl 4-hydroxybenzoate and 1 g of propyl4-hydroxybenzoate are dissolved in 4 l of boiling purified water. In 3 lof this solution are dissolved first 10 g of 2,3-dihydroxybutanedioicacid and thereafter 20 g of the A.I. The latter solution is combinedwith the remaining part of the former solution and 12 l of1,2,3-propanetriol and 3 l of sorbitol 70% solution are added thereto.40 g of sodium saccharin are dissolved in 0.5 l of water and 2 ml ofraspberry and 2 ml of gooseberry essence are added. The latter solutionis combined with the former, water is added q.s. to a volume of 20 lproviding an oral solution comprising 5 mg of the A.I. per teaspoonful(5 ml). The resulting solution is filled in suitable containers.

EXAMPLE D.2 Capsules

[0178] 20 g of the A.I., 6 g sodium lauryl sulfate, 56 g starch, 56 glactose, 0.8 g colloidal silicon dioxide, and 1.2 g magnesium stearateare vigorously stirred together. The resulting mixture is subsequentlyfilled into 1000 suitable hardened gelatin capsules, each comprising 20mg of the A.I.

EXAMPLE D.3 Film-Coated Tablets

[0179] Preparation of Tablet Core

[0180] A mixture of 100 g of the A.I., 570 g lactose and 200 g starch ismixed well and thereafter humidified with a solution of 5 g sodiumdodecyl sulfate and 10 g polyvinyl-pyrrolidone in about 200 ml of water.The wet powder mixture is sieved, dried and sieved again. Then there areadded 100 g microcrystalline cellulose and 15 g hydrogenated vegetableoil. The whole is mixed well and compressed into tablets, giving 10,000tablets, each comprising 10 mg of the active ingredient.

[0181] Coating

[0182] To a solution of 10 g methyl cellulose in 75 ml of denaturatedethanol there is added a solution of 5 g of ethyl cellulose in 150 ml ofdichloromethane. Then there are added 75 ml of dichloromethane and 2.5ml 1,2,3-propanetriol. 10 g of polyethylene glycol is molten anddissolved in 75 ml of dichloromethane. The latter solution is added tothe former and then there are added 2.5 g of magnesium octadecanoate, 5g of polyvinylpyrrolidone and 30 ml of concen-trated colour suspensionand the whole is homogenated. The tablet cores are coated with the thusobtained mixture in a coating apparatus.

EXAMPLE D.4 Injectable Solution

[0183] 1.8 g methyl 4-hydroxybenzoate and 0.2 g propyl 4-hydroxybenzoatewere dissolved in about 0.5 l of boiling water for injection. Aftercooling to about 50° C. there were added while stirring 4 g lactic acid,0.05 g propylene glycol and 4 g of the A.I. The solution was cooled toroom temperature and supplemented with water for injection q.s. ad 1 lvolume, giving a solution of 4 mg/ml of A.I. The solution was sterilizedby filtration and filled in sterile containers.

EXAMPLE D.5 Suppositories

[0184] 3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 ml polyethylene glycol 400. 12 Gramssurfactant and 300 grams triglycerides were molten together. The lattermixture was mixed well with the former solution. The thus obtainedmixture was poured into moulds at a temperature of 37-38° C. to form 100suppositories each containing 30 mg/ml of the A.I.

1. A compound of formula (I)

a N-oxide form, a pharmaceutically acceptable addition salt or astereochemically isomeric form thereof, wherein the dotted line is anoptional bond; n is 1 or 2; R¹ is hydrogen; halo; formyl; C₁₋₄alkyl;C₁₋₄alkyl substituted with 1 or 2 substituents each independentlyselected from hydroxy, C₁₋₄alkyloxy, C₁₋₄alkylcarbonyloxy, imidazolyl,thiazolyl or oxazolyl; or a radical of formula —X—CO—OR⁵ (a-1);—X—CO—NR⁶R⁷ (a-2); or —X—CO—R¹⁰ (a-3);

wherein —X— is a direct bond, C₁₋₄alkanediyl or C₂₋₆alkenediyl; R⁵ ishydrogen; C₁₋₁₂alkyl; Ar; Het; C₁₋₆alkyl substituted with C₁₋₄alkyloxy,C₁₋₄alkyloxycarbonylC₁₋₄alkyloxy, Ar or Het; R⁶ and R⁷ eachindependently are hydrogen or C₁₋₄alkyl; R¹⁰ is imidazolyl, thiazolyl oroxazolyl; R² is hydrogen, halo, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,C₁₋₄alkyloxycarbonyl, carboxyl, formyl or phenyl; R³ is hydrogen,C₁₋₄alkyl or C₁₋₄alkyloxy; R⁴ is hydrogen, halo, C₁₋₄alkyl, C₁₋₄alkyloxyor haloC₁₋₄alkyl; Z is Z¹ or Z²; wherein Z¹ is a bivalent radical offormula —CH₂—, —CH₂—CH₂— or —CH═CH—; provided that when the dotted lineis a bond, then Z¹ is other than —CH₂—; Z² is a bivalent radical offormula —CHOH—CH₂—, —O—CH₂—, —C(═O)—CH₂— or —C(═NOH)—CH₂—; —A—B— is abivalent radical of formula —Y—CR⁸═CH— (b-1); —CH═CR⁸—Y— (b-2);—CH═CR⁸—CH═CH— (b-3); —CH═CH—CR⁸═CH— (b-4); or —CH═CH—CH═CR⁸— (b-5);

wherein each R⁸ independently is hydrogen, halo, C₁₋₄alkyl,C₁₋₄alkyloxy, hydroxyC₁₋₄alkyl, hydroxycarbonylC₁₋₄alkyl, formyl,carboxyl, ethenyl substituted with carboxyl, or ethenyl substituted withC₁₋₄alkyloxycarbonyl; each Y independently is a bivalent radical offormula —O—, —S— or —NR⁹—; wherein R⁹ is hydrogen, C₁₋₄alkyl orC₁₋₄alkylcarbonyl; —A¹— is a direct bond; C₁₋₆alkanediyl;C₁₋₆alkanediyl-oxy-C₁₋₆alkanediyl; C₁₋₆alkanediyloxy; carbonyl;C₁₋₆alkanediylcarbonyl; C₁₋₆alkanediyloxy substituted with hydroxy; orC₁₋₆alkanediyl substituted with hydroxy or ═NOH; —A²— is a direct bondor C₁₋₆alkanediyl; Q is phenyl; phenyl substituted with one or twosubstituents selected from hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy orhaloC₁₋₄alkyl; naphthalenyl; naphthalenyl substituted with one or twosubstituents selected from hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy orhaloC₁₋₄alkyl; pyridinyl; pyridinyl substituted with one or twosubstituents selected from hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy orhaloC₁₋₄alkyl; quinolinyl; or quinolinyl substituted with one or twosubstituents selected from hydrogen, hydroxy, C₁₋₄alkyl, C₁₋₄alkyloxy orhaloC₁₋₄alkyl; Ar is phenyl or phenyl substituted with 1, 2 or 3substituents each independently selected from hydrogen, halo, C₁₋₄alkylor C₁₋₄alkyloxy; Het is furanyl; furanyl substituted with C₁₋₄alkyl,C₁₋₄alkyloxy or hydroxyC₁₋₄alkyl; oxazolyl; oxazolyl substituted withC₁₋₄alkyl or C₁₋₄alkyloxy; or quinolinyl.
 2. A compound according toclaim 1 wherein —A—B— is a bivalent radical of formula (b-2), (b-3) or(b-4); Z is Z¹ wherein Z¹ is a bivalent radical of formula —CH₂—CH₂— or—CH₂—, or Z is Z² wherein Z² is a bivalent radical of formula—C(═O)—CH₂—; —A¹— is C₁₋₆alkanediyl, C₁₋₆alkanediyloxy, carbonyl,C₁₋₆alkanediyloxy substituted with hydroxy, or C₁₋₆alkanediylsubstituted with hydroxy; —A²— is a direct bond or C₁₋₆alkanediyl; Q isphenyl, naphthalenyl, pyridinyl, quinolinyl, phenyl substituted withhalo or C₁₋₆alkyloxy, naphthalenyl substituted with halo orC₁₋₆alkyloxy, pyridinyl substituted with halo or C₁₋₆alkyloxy orquinolinyl substituted with halo or C₁₋₆alkyloxy; R¹ is hydrogen, halo,formyl, C₁₋₄alkyl substituted with hydroxy, or a radical of formula(a-1) wherein X is a direct bond or C₁₋₄alkanediyl and R⁵ is hydrogen,C₁₋₁₂alkyl, Ar or C₁₋₆alkyl substituted with Het; R² is hydrogen, halo,C₁₋₄alkyl, formyl, hydroxyC₁₋₄alkyl or C₁₋₄alkyloxycarbonyl; R³ ishydrogen; R⁴ is hydrogen, halo, C₁₋₆alkyl or C₁₋₆alkyloxy and the dottedline is a bond.
 3. A compound according to any of claims 1 to 2 whereinZ is —CH₂—CH₂—; —A—B— is —CH═CH—CH═CH—; —A¹— is —CH₂—CH₂—, —CH₂—CH₂—CH₂—or —O—CH₂—CH₂—; —A²— is —CH₂—; R¹ is hydrogen, halo, formyl or a radicalof formula (a-1) wherein X is a direct bond and R⁵ is hydrogen,C₁₋₁₂alkyl, Ar or C₁₋₆alkyl substituted with Het; R² is hydrogen,C₁₋₄alkyl, formyl or C₁₋₄alkyloxycarbonyl; R³ is hydrogen; R⁴ ishydrogen or C₁₋₄alkyloxy and the dotted line is a bond.
 4. A compoundaccording to claim 1 wherein the compound is methyl6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;or dimethyl6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-2,3-dicarboxylate;or ethyl6,11-dihydro-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;methyl11-[1-[[3,5-dimethoxy-4-(2-quinolinylmethoxy)phenyl]methyl]-4-piperidinylidene]-6,11-dihydro-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;methyl6,11-dihydro-11-[1-[3-[4-(2-quinolinylmethoxy)phenyl]propyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate; methyl6,11-dihydro-11-[1-[2-[4-(2-naphthalenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;methyl6,11-dihydro-11-[1-[2-[4-(phenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;and methyl6,11-dihydro-11-[1-[2-[4-(1-naphthalenylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-carboxylate;the stereoisomeric forms and the pharmaceutically acceptable additionsalts thereof.
 5. A pharmaceutical composition comprising apharmaceutically acceptable carrier, and as active ingredient atherapeutically effective amount of a compound as described in any oneof claims 1 to
 4. 6. A process for preparing a pharmaceuticalcomposition as claimed in claim 5 characterized in that atherapeutically active amount of a compound as claimed in any one ofclaims 1 to 4 is intimately mixed with a pharmaceutically acceptablecarrier.
 7. A compound according to any one of claims 1 to 4 for use asa medicine.
 8. A product containing a) a composition comprising apharmaceutically effective amount of a compound according to any ofclaims 1 to 4 and a pharmaceutically acceptable carrier; and b) acomposition comprising a pharmaceutically effective amount of ananti-neoplastic agent and a pharmaceutically acceptable carrier, as acombined preparation for simultaneous, separate or sequential use inanti-neoplastic therapy.
 9. A product containing a) a compositioncomprising a pharmaceutically effective amount of a compound accordingto any of claims 1 to 4 and a pharmaceutically acceptable carrier; b)and a composition comprising a pharmaceutically effective amount of apharmaceutical agent useful to treat conditions caused by pathogens anda pharmaceutically acceptable carrier, as a combined preparation forsimultaneous, separate or sequential use in the treatment of conditionscaused by pathogens.
 10. A compound of formula (II-b)

a pharmaceutically acceptable acid addition salt or a stereochemicallyisomeric form thereof wherein n is 1 or 2; R⁴ is hydrogen, halo,C₁₋₄alkyl, C₁₋₄alkyloxy or haloC₁₋₄alkyl; Q¹ is phenyl substituted withone or two substituents selected from hydrogen, hydroxy, C₁₋₄alkyl,C_(alkyloxy or haloC) ₁₋₄alkyl; naphthalenyl; naphthalenyl substitutedwith one or two substituents selected from hydrogen, hydroxy, C₁₋₄alkyl,C₁₋₄alkyloxy or haloC₁₋₄alkyl; pyridinyl; pyridinyl substituted with oneor two substituents selected from hydrogen, hydroxy, C₁₋₄alkyl,C₁₋₄alkyloxy or haloC₁₋₄alkyl; quinolinyl; or quinolinyl substitutedwith one or two substituents selected from hydrogen, hydroxy, C₁₋₄alkyl,C₁₋₄alkyloxy or haloC₁₋₄alkyl; —A^(1′)— is C₁₋₆alkanediyl,C₁₋₆alkanediyloxy or C₁₋₆alkanediyloxyC₁₋₆alkanediyl; —A²— is a directbond or C₁₋₆alkanediyl; and W is halo, methanesulfonyloxy orbenzenesulfonyloxy.
 11. A process for preparing a compound of formula(T) characterized by a) reacting a reagent of formula (III), wherein Trepresents the fused imidazole moiety,

 with an intermediate of formula (II), wherein W represents anappropriate leaving group;

b) O-alkylating an intermediate of formula (IV), wherein W represents anappropriate leaving group, with a reagent of formula (V);

c) reductively N-alkylating in intermediate of formula (III) with anintermediate of formula (XIX), wherein A^(1″) represents a direct bond,C₁₋₅ alkanediyl, C₁₋₅alkanediyloxy or a C₁₋₆alkanediyl-oxyC₁₋₅alkanediylmoiety, thereby yielding compounds of formula (I-i) wherein —A^(1′)—represents C₁₋₆alkanediyl, C₁₋₆alkanediyloxy orC₁₋₆alkanediyloxyC₁₋₆alkanediyl;

d) converting a compound of formula (I-a), wherein M represents thesubstituted piperidine moiety,

 into a compound of formula (I-b), according to art-known esterificationmethods;

e) reacting a compound of formula (I-a-1) with an oxidizing agent in areaction-inert solvent;

f) esterification of compound of formula (I-d) to a compound of formula(I-e);

g) hydrolyzing a compound of formula (I-e) to a compound of formula(I-d) in the presence of an acid or a base; h) reacting a compound offormula (I-c) with methyl methylthiomethyl sulfoxide in a suitablesolvent, thus yielding a compound of formula (I-f);

i) reacting a compound of formula (I-c) with an alcohol of formula R⁵OHin the presence of acetic acid, MnO₂ and NaCN, thus yielding a compoundof formula (I-e-1);

j) reacting a compound of formula (I-g) with a reducing agent in areaction-inert solvent;

 wherein in the above reaction schemes the radicals R¹, R², R³, R⁴, Z,—A—B—, A¹, A² and Q are as defined in claim 1 and W is an appropriateleaving group;  or, converting compounds of formula (I) into each otherfollowing art-known transformation reactions; and further, if desired,converting the compounds of formula (I), into an acid addition salt bytreatment with an acid, or into a base addition salt by treatment with abase, or conversely, converting the acid addition salt form into thefree base by treatment with alkali, or converting the base addition saltinto the free acid by treatment with acid; and, if desired, preparingN-oxide and/or stereochemically isomeric forms thereof.
 12. A processfor preparing a compound as claimed in claim 10 wherein an intermediateof formula (VI) is O-alkylated with an intermediate of formula (IV), ina reaction-inert solvent and subsequently the hydroxy group of anintermediate of formula (VII) is converted into a leaving group W;

in the above reaction scheme n, R⁴, Q¹, A^(1′), A² and W are as definedin claim 10 and W¹ is an appropriate leaving group; or an intermediatecompound of formula (II-a) is converted into an acid addition salt, orconversely, an acid addition salt is converted into a free base formwith alkali; and, if desired, preparing stereochemically isomeric formsthereof.